subjects. The criteria for at-risk patients who would benefit from lungcancerscreening have not been established yet in Korea. Therefore, it is likely that a per- centage of the study population is not truly at-risk for malignancy along with those that received voluntary testing. As a result, our cohort of patients may be differ- ent from those used in previous LDCT-based studies. Secondly, we were unable to obtain data regarding smoking status at the time of the study. Since most can- cers are related to smoking, it is important to know how many smokers were included in the study population. Additionally, there may be radiological features of ITNs that are associated with smoking history.
Molecular biomarkers are potentially useful adjuncts to LDCT for lungcancerscreening, either by further delin- eating patient risk prior to LDCT, or assessing malignant risk of positive LDCT findings [1, 4, 6, 9, 10]. The per- formance of any test also depends upon the prior prob- ability of the condition in the population being sampled and this varies considerably [11, 12]. Biomarkers may be generated from cancer cells, the tumor microenviron- ment, or the host response to cancer [4, 13]. Various mo- lecular factors that are implicated in lung carcinogenesis have been evaluated as prognostic and diagnostic bio- markers, such as markers of apoptosis, cellular adhesion, cellular growth, and tumor proliferation [10, 14]. Epigen- etic markers such as DNA methylation, miRNAs, nucleo- some remodeling, and histone modifications have also been investigated [10, 13, 14]. Biomarkers may be sampled from many different bodily sources, including whole blood, serum, plasma, bronchial brushings, and sputum [13, 14]. Circulating blood-based and serum-based bio- markers are a convenient compartment to sample as they are relatively easy and inexpensive to collect [4, 6, 9].
The National LungScreening Trial (NLST) in the United States (2) demonstrated and the LungCancerScreening Trial Pilot in the United Kingdom (3) suggested that screening with low dose CT scans (LDCT) significantly reduces mortality from lungcancer among high risk individuals aged 55 to 74 years as compared to chest x-rays. In the NLST, there were potential harms associated with LDCT screening (4). Averaged across three annual lung scans, 11.2% of screens were followed by an extra scan (with additional radiation), 0.9% of scans led to diagnosis of lungcancer (10-15% of which would not have appeared during the patient’s remaining life), 0.5% of scans led to biopsy or bronchoscopy that did not find cancer, and 0.3% of scans led to surgery that did not reveal lungcancer.
Smoking and other environmental factors are well- known risk factors that are targeted in primordial or primary prevention of lungcancer. As screening is a secondary prevention approach, secular variation in these risk factors may have non-linear effects on lungcancer incidence  and, thus, may complicate the predicted effectiveness of screening. In addition, can- cer screening motivated smokers to quit, as ex-smokers concerned with their health status were more willing to participate in the United Kingdom LungCancerScreening Trial . Therefore, socio-behaviors should be carefully monitored and considered to take advan- tage of combining programs such as tobacco control and lungcancerscreening. A third important factor is that the spectrum of cancer pathological type may change along with changes in environmental risk fac- tors, which further complicates the issue. Therefore, future research should also be placed in a broader con- text and investigate the impact of policies on tobacco control and environment protection, which are cur- rently undergoing significant changes in China.
The goal of a screening program is to detect tumors in a stage when patients are asymptomatic, treatment is most successful and treatment costs are lower. 5 Screening for lungcancer is feasible for three different reasons. 6,7 First, lungcancer has a poor prognosis with an average survival rate of 17%. 8 A significant increase in survival rate can be achieved in case a tumor is detected in early stage. Stage I has an average five-year survival rate of 65.9% versus 0.1% of a stage IV tumor. 9,10 Currently, only 15% of tumors are detected in stage I to III. 1 A second opportunity for screening is the easy identified risk group. Tobacco smoking is the most important cause of lungcancer. The probability for heavy smokers to develop lungcancer is 33% higher when compared to non-smokers. 11–13 The American Cancer Society reports a life time probability of developing lungcancer of 6.3% for women and 7.7% for men. Smoking accounts for 87% of lungcancer deaths among men and 70% of lungcancer deaths among women. 14 The third reason for introducing screening is the decrease in short-term costs in case tumors can be detected in an earlier stage. Healthcare costs attributable to lungcancer amount to 8.4% ($449.5 million) and 9.7% ($12.1 billion) of total cancer costs in the Netherlands and the US respectively. 15,16 This is mostly made up out of treatment costs and depends strongly on tumor stage. In 2000, treatment costs of a 72 year old patient in the US in stage IV were 23.8% higher than treatment costs in stage I/II. 7 Several other countries have started lungcancerscreening trials. 3,17–22 The NEderlands-Leuvens
In this paper, we report baseline results from UK t community-based, LDCT lungcancerscreening service, utilising mobile CT scanners. Our approach was to target high-risk individuals in deprived areas of Manchester, with an invitation to convenient community- based L H C s with immediate access to CT. We selected the screened population according to individual risk scores (PLCO M2012 ). The prevalence of lungcancer was
A number of screening trials for early detection of lungcancer have been, or are be- ing, conducted using both chest X-ray (CXR) and low-dose computed tomography (LDCT) screening. The latter is the superior method; it is more sensitive than CXR and has enabled detection of small, asymptomatic lung tumors. Early diagnosis by LDCT screening led to a substantial 20% reduction in lungcancer-specific mortality and a sig- nificant 6.7% reduction in all-cause mortality in the US National LungScreening Trial . A lungcancerscreening program with LDCT is a complex endeavor with the pur- pose of identifying asymptomatic patients affected by lungcancer at an early stage, thereby maximizing the odds of a curative treatment without causing harm to healthy participants. As LDCT screening is currently being implemented on an extensive, population-wide, scale in several countries [5, 6], it seems probable that lungcancerscreening will enter the health care arena, irrespective of whether it is privately or pub- lically funded. However, several expert panels have highlighted the need for further im- provements of LDCT screening before implementation .
The National LungScreening Trial in the United States and the LungCancerScreening Trial in the United Kingdom have demonstrated that screening with low dose computed tomography (LDCT) scans significantly reduces mortality from lungcancer [1, 2]. Optimal methods to identify potentially eligible asymptomatic patients in primary care are not known, although web- based technologies may be useful. For example, soft- ware is now available which allows patients attending primary care appointments to receive and respond to electronic questionnaires before their consultation. Re- sponses to electronic questionnaires can then be used for different purposes such as determining eligibility for clin- ical studies, populating the electronic medical record (EMR) and providing an opportunity for ‘just-in-time’ counseling by primary care providers (PCPs). For example, in New Zealand, researchers developed an electronic tool for primary care called eCHAT (electronic case-finding and help assessment tool) . The tool was used by pa- tients in the waiting room prior to a visit or via the Inter- net in the community. The goal of the tool was to encourage active participation by patients in decision- making and self-management practices.
For decades, lungcancer has been the most common cancer in terms of both incidence and mortality. There has been very little improvement in the prognosis of lungcancer. Early treatment following early diagnosis is considered to have potential for development. The National LungScreening Trial (NLST), a large, well-designed randomized controlled trial, evaluated low-dose computed tomography (LDCT) as a screening tool for lungcancer. Compared with chest X-ray, annual LDCT screening reduced death from lungcancer and overall mortality by 20 and 6.7 %, respectively, in high-risk people aged 55 – 74 years. Several smaller trials of LDCT screening are under way, but none are sufficiently powered to detect a 20 % reduction in lungcancer death. Thus, it is very unlikely that the NLST results will be replicated. In addition, the NLST raises several issues related to screening, such as the high false-positive rate, overdiagnosis and cost. Healthcare providers and systems are now left with the question of whether the available findings should be translated into practice. We present the main reasons for implementing lungcancerscreening in high-risk adults and discuss the main issues related to lungcancerscreening. We stress the importance of eligibility criteria, smoking cessation programs, primary care physicians, and informed-decision making should lungcancerscreening be implemented. Seven years ago, we were waiting for the results of trials. Such evidence is now available. Similar to almost all other cancer screens, uncertainties exist and persist even after recent scientific efforts and data. We believe that by staying within the characteristics of the original trial and appropriately sharing the evidence as well as the uncertainties, it is reasonable to implement a LDCT lungcancerscreening program for smokers and former smokers.
Nine randomized controlled trials evaluating LDCT to screen lungcancer are ongoing worldwide [34-45].  The LungScreening Study (LSS) was initiated in 2000, whereas the NLST published the first trial results  showing a relative 20% reduction in lungcancer specific deaths among participants screened with LDCT versus CXR. The NLST trial in 2002 recruited 53,454 high-risk participants aged 55 or older to undergo three screenings at 1-year intervals with either LDCT or CXR. The LDCT group noted 247 lungcancer deaths per 100,000 person- years compared to 309 deaths in the CXR group. The NLST trial was acclaimed as a major breakthrough in the lungcancerscreening field and showed clear evidence of a significant reduction in lungcancer deaths, but raised concerns regarding how to define the high-risk popula- tions and who would benefit from LDCT screening; what is the optimal time to start LDCT screening; how long to follow patients and what intervals to screen; and lastly the overwhelming financial cost of LDCT screening. Time and further research may provide definitive answers regarding the impact of LDCT screening on lungcancer specific mortality at the population level. Additional Table 1 LDCT in lungcancerscreening
Bach et al. showed increase of lungcancer risk in associ- ation to asbestos exposure in participants of lungcancerscreening trials . In our study, screenees with pleural plaques showed higher risk of lungcancer mortality com- pared to the remainder screenees. We underline that screenees with pleural plaques were diagnosed with ad- vanced stage lungcancer. Hence, we suggest that in- creased mortality could have been driven by a more aggressive pattern of lungcancer in this group of screen- ees. Again, it is apparent that assessment of pleural pla- ques in lungcancerscreening participant contributes to the detection of subjects with minor or unknown exposure. For this purpose, the objective assessment of pleural abnormal- ities could be regarded as potential marker of increased risk of lungcancer associated to asbestos exposure, and should be investigated for post-test refinement of subjective risk of lungcancer. Furthermore, from a demographic point of view, detection of pleural plaques in screenees that are not aware of the exposure should prompt active investigation of environmental exposure to asbestos in specific areas.
The European position statement on lungcancerscreening re- commends low dose computed tomography for high risk populations, with smoking cessation advice oﬀered alongside . The prevalence of tobacco smoking ranges from 10 to 38% between European countries . In England, 17% of adults smoke . However, data from lungscreening trials suggests smoking prevalence is likely to be higher among lungscreening attendees [4–6]; within the UK LungCancerScreening (UKLS) pilot trial, 38.3% of the screening arm were current smokers . Tobacco is the single greatest contributor to cancer burden in the European Union . However, health behaviours tend to cluster, meaning smokers are more likely to engage in other cancer risk beha- viours, including increased alcohol consumption and eating an un- healthy diet [8,9]. These modiﬁable behaviours contribute to many non-communicable diseases including cancer, cardiovascular and
The results of our physician survey have some similari- ties and differences to the Hoffman and Ersek studies. First, the proportion of respondents in our survey who agreed or strongly agreed that lungcancerscreening is beneficial for patients was lower than that in the South Carolina group (35%–40% versus 75%). Second, unlike the South Carolina study in which 31% of respondents agreed or strongly agreed that LDCT screening is cost-effective, only 6.9% of residents and 19.5% of attending PCPs in our study perceived lung can- cer screening as being cost-effective. Similar to the Hoffman study, cost to patients was the most frequently reported barrier to lungcancerscreening among our respondents. While lungcancerscreening with LDCT is covered by most of the insur- ance plans for those patients meeting the high-risk definition, the work-up of pulmonary nodules or incidental findings will likely incur out-of-pocket expenses for the patient. Third, providers in all three studies raised concern about the high false-positive rate. In a retrospective analysis, application of the American College of Radiology Lung-RADS to NLST data suggests that use of Lung-RADS may potentially reduce the false-positive rates, 27 which may alleviate some provider
The notion that patient factors may lead FPs to override their decision to follow guidelines is further supported by other findings of this study. When asked in a single- item opinion-based question if CXR is recommended for lungcancerscreening, 18 participants responded that they perceived that CXR was recommended; yet, when faced with an uncomplicated patient scenario, 23 indicated they would order a CXR. The fact that 48% screened in the Uncomplicated Scenario contrary to prevailing national guidelines, suggests that there must be other factors (besides the complicating factors assessed in this study) influencing their decision-making. In summary, presence of multiple factors (patient anxiety, expectation, positive family history of lungcancer, poor patient-physician relationship) significantly influenced FPs decisions to screen and over- rides their perception of guidelines. These findings illustrate the influence of patient factors on evidence-based medicine for lungcancerscreening decision-making.
promoter region in their tumor suppressor genes [4, 9, 10]. In smokers, both oral and lung tissues are exposed to the same carcinogens and suffer from the same kind of molecular and cellular modifications. Using polymerase chain reaction (PCR), Bhutani and his associates compared tumor suppressor genes p16 in oral mucosa and bronchial mucosa of 125 cases of healthy long-term smokers. In bronchial tissue, the methylation rate in p16, FHIT, and two simultaneous promoters were found to be 23%, 17% and 35% respectively. Methylation rate in p16, FHIT, and two simultaneous promoters were 19%, 15% and 31% respectively in oral tis- sue. The research demonstrated that modifica- tions of anti-oncogenes and promoters in the bronchial tissue had a significant correlation to that in oral tissue (P < 0.0001) . Lung tissue changes caused by smoking can be evaluated by examinations of these changes in oral cavity mucous epithelium. The tumor suppressor genes in oral mucosa and pulmonary epitheli- um of chronic smokers likely undergo similar biological changes. This fact lays the founda- tion for the feasibility of using oral mucosa as a lungcancerscreening method.
Some risk assessment models that incorpo- rate additional risk factors have been devel- oped and demonstrated to improve lungcancerscreening efficiency in North America and the UK, including PLCO m2012 and Liver- pool Lung Project Model. 3 4 The performance of these models has been evaluated in several studies in the USA, UK, Canada, Germany and Australia, but have not been validated in South America. 3–10
In the UK in 1999 lungcancer was responsible for 34 240 deaths (22% of all cancer deaths). Proposals for a randomized controlled trial have been developed by the UK Cancer Coordinating Committee for Research — Lung (UKCCCR). The primary research objective of the UK trial is to determine whether lungcancerscreening using low-dose Spiral CT reduces mor- tality from lungcancer. To address this issue a random- ized controlled trial of Spiral CT vs. no screening in smokers, 60 years and over, is proposed, with lungcancer mortality as the primary end-point. Smoking cessation will be oﬀered to both the screened and unscreened group. Initially a pilot trial of 2000 individ- uals is planned, the purpose of which is to determine the feasibility, compliance and costs of a large randomized controlled trial. There will be six participating centres in the pilot.
group tobacco cessation counseling were trained to administer an educational intervention about LCS. The intervention was administered to 25 participants during May 2019 who completed surveys that assessed how much the information provided helped with understanding various aspects of lungcancerscreening including benefits, risks, eligibility criteria, and insurance coverage. The intervention also provided information on how to learn more about LCS and assessed the acceptability of the information.
or CXR was classified as a positive screen. Of the studies performed, 24.2% of LDCTs and 6.9% of radiographs were positive, with 39% of individuals in the LDCT group and 16% of those in the radiograph group having at least one positive screen during the 3-year period. Of these abnormalities 96.4% were false-positive findings (i.e. they did not lead to a diagnosis of cancer). Although most positive findings were resolved by further imaging, 11% were followed by an invasive diagnostic procedure. The rate of procedure-related complications was low (1.4% of positive screenees in the LDCT group and 1.6% of those in the CXR group experienced a complication). The trial was stopped prematurely as an interim analysis demonstrated a statistically significant reduction of 20% in LC-specific mortality and 6.7% in all- cause mortality in the LDCT arm. The number needed to screen with LDCT to avoid one LC death was 320. 
Most focus group participants needed detailed explana- tion of the term ‘overdiagnosis’, though one participant who had a history of prostate cancer described the ‘tiger’ and the ‘sleepy’ cancers, and said ‘But if you get the tiger … you’re in trouble’ (M4, FG68_CS_ED−). Fear of cancer, perhaps accounted for why many felt ‘probably, it wouldn’t stop me being screened’ (M6, FG65_FS_ED+). Some partic- ipants were concerned about being ‘happy, smiley… and suddenly … get told, you’ve got cancer’ (M6, FG64_FS_ED+). Despite this, many felt they would rather know about the cancer and have the option not to treat it. When suggested that it may not always be possible to deter- mine prognosis, participants felt ‘you can’t take that risk’ (F3, FG68_CS_ED−) of not treating. HCPs also acknowl- edged that patients often ‘don’t necessarily want to just say “oh leave it to be”’ (INT51_RP). One RP felt overdiagnosis was a ‘fallacy’ (INT72_RP) and supported the idea that expectant management of some ‘ground glass’ pulmo- nary nodules would reduce overdiagnosis.